J Pharmacol Sci. 2026 Oct;162(2):117-129. doi: 10.1016/j.jphs.2026.07.005. Epub 2026 Jul 30.
ABSTRACT
Ischemic stroke (IS) triggers neuroinflammation that drives neuronal dysfunction and tissue injury. Resident central nervous system macrophages critically contribute to IS-induced injury through inflammatory infiltration and cytokine secretion. Methylophiopogonone A (MOA), a flavonoid from Ophiopogon japonicus, protects against heart and liver injury, but its role in IS-induced brain injury remains unclear. Here, we investigated whether MOA attenuates neuroinflammation and brain injury in a mouse IS model and explored its molecular mechanism in macrophage inflammatory activation. MOA treatment reduced brain infarct volume and neurological deficits in transient middle cerebral artery occlusion (tMCAO) mice. It also significantly decreased the secretion of pro-inflammatory cytokine (IL-2, IL-6, IL-1β, IL-18, TNF-α) and TGF-β, and suppressed M1 activation marker expression (IL-6, TNF-α, iNOS) in brain tissue. Immunofluorescence revealed that MOA reduced neutrophil and monocyte-derived macrophage infiltration into ischemic lesions, inhibited macrophage iNOS expression, and suppressed NF-κB p65 phosphorylation. Mechanistically, MOA directly bound the NF-κB p65 subunit, inhibiting its phosphorylation and nuclear translocation in macrophages. This suppressed M1 activation gene expression (IL-6, TNF-α, iNOS) and reduced pro-inflammatory cytokine secretion (IL-6, IL-1β, IL-18, TNF-α). Collectively, these findings demonstrate that MOA protects against tMCAO-induced ischemic injury by inhibiting NF-κB signaling-mediated M1 activation of macrophages and reducing the infiltration of both macrophages and neutrophils. These results position MOA as a potential therapeutic agent for neuroinflammation and brain injury associated with IS.
PMID:42632746 | DOI:10.1016/j.jphs.2026.07.005